Gene-targeted deletion of neurofibromin enhances the expression of a transient outward K+ current in Schwann cells: A protein kinase A-mediated mechanism

Yanfang Xu, Nipavan Chiamvimonvat, Ana Vazquez, Shailaja Akunuru, Nancy Ratner, Ebenezer N Yamoah

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Mutations in the neurofibromatosis type 1 gene predispose patients to develop benign peripheral nerve tumors (neurofibromas) containing Schwann cells (SCs). SCs from neurofibromatosis type-1 gene (Nf1) null mutant mice showed increased levels of Ras-GTP and cAMP. The proliferation and differentiation of SCs are regulated by Ras-GTP and cAMP-mediated signaling, which have been linked to expression of K+ channels. We investigated the differential expression of K+ currents in Nf1 null mutant SCs (Nf1-/-) and their wild-type (Nf1+/+) counterparts and determined the mechanisms underlying the differences. The current densities of the sustained component of K+ currents were similar in the two genotypes. However, Nf1-/- SCs showed a significant increase (∼1.5-fold) in a 4-aminopyridine-sensitive transient outward K+ current (IA). Nonstationary fluctuation analysis revealed a significant increase in the number of functional channels in the null mutant cells. When the involvement of the Ras pathway in the modulation of the K+ current was examined using adenoviral-mediated gene transfer of a dominant-negative H-Ras N17 or the known H-Ras inhibitor (L-739,749), an additional increase in IA was observed. In contrast, protein kinase A (PKA) inhibitors, H89 and [PKI(2-22)amide] attenuated the enhancement of the current in the Nf1-/- cells, suggesting that the increase in IA was mediated via activation of protein kinase A. The unitary conductance of the channel underlying IA was unaltered by inhibitors of PKA. Activation of IA is thus negatively regulated by Ras-GTP and positively regulated by PKA.

Original languageEnglish (US)
Pages (from-to)9194-9202
Number of pages9
JournalJournal of Neuroscience
Volume22
Issue number21
StatePublished - Nov 1 2002

Keywords

  • Glia
  • K channels
  • Neurofibromin NF1
  • Protein kinase A
  • Schwann cells
  • Voltage clamp

ASJC Scopus subject areas

  • Neuroscience(all)

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